P2X7 receptor inhibition increases CNTF in the subventricular zone, but not neurogenesis or neuroprotection after stroke in adult mice.

Abstract

Increasing endogenous ciliary neurotrophic factor (CNTF) expression with a pharmacological agent might be beneficial after stroke as CNTF both promotes neurogenesis and, separately, is neuroprotective. P2X7 purinergic receptor inhibition is neuroprotective in rats and increases CNTF release in rat CMT1A Schwann cells. We, first, investigated the role of P2X7 in regulating CNTF and neurogenesis in adult mouse subventricular zone (SVZ). CNTF expression was increased by daily intravenous injections of the P2X7 antagonist Brilliant Blue G (BBG) in naïve C57BL/6 or Balb/c mice over 3 days. Despite the ∼40-60 % increase or decrease in CNTF with BBG or the agonist BzATP, respectively, the number of proliferated BrdU+SVZ nuclei did not change. BBG failed to increase FGF2, which is involved in CNTF-regulated neurogenesis, but induced IL-6, LIF, and EGF, which are known to reduce SVZ proliferation. Injections of IL-6 next to the SVZ induced CNTF and FGF2, but not proliferation, suggesting that IL-6 counteracts their neurogenesis-inducing effects. Following ischemic injury of the striatum by middle cerebral artery occlusion (MCAO), a 3-day BBG treatment increased CNTF in the medial penumbra containing the SVZ. BBG also induced CNTF and LIF, which are known to be protective following stroke, in the whole striatum after MCAO, but not GDNF or BDNF. However, BBG treatment did not reduce the lesion area or apoptosis in the penumbra. Even so, this study shows that P2X7 can be targeted with systemic drug treatments to differentially regulate neurotrophic factors in the brain following stroke.

• Authors: Seong Su Kang, Matthew Phillip Keasey, Theo Hagg
• Journal: Translational stroke research (Transl Stroke Res) Vol. 4 Issue 5 Pg. 533-45 (Oct 2013) ISSN: 1868-601X [Electronic] United States
• PMID: 24312160 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Affinity Labels
• Ciliary Neurotrophic Factor
• Cytokines
• Indicators and Reagents
• Neuroprotective Agents
• Purinergic P2X Receptor Antagonists
• Receptors, Purinergic P2X7
• Rosaniline Dyes
• 3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate
• Adenosine Triphosphate
• coomassie Brilliant Blue

Topics

• Adenosine Triphosphate (analogs & derivatives, pharmacology)
• Affinity Labels (pharmacology)
• Animals
• Ciliary Neurotrophic Factor (biosynthesis)
• Cytokines (metabolism)
• Disease Models, Animal
• Indicators and Reagents (pharmacology)
• Infarction, Middle Cerebral Artery (metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Neurogenesis (drug effects)
• Neuroprotective Agents (pharmacology)
• Purinergic P2X Receptor Antagonists (pharmacology)
• Receptors, Purinergic P2X7 (metabolism)
• Rosaniline Dyes (pharmacology)
• Stroke (metabolism)